FoxO1 in Gestational Diabetes

FoxO1 在妊娠糖尿病中的作用

• 批准号: 10418783
• 负责人: HENGJIANG HENRY DONG
• 金额: $ 39.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418783
• 关键词: Address; Adverse effects; Affect; Beta Cell; Blood; Blood Glucose; Cellular Metabolic Process; ChIP-seq; Complication; Cues; Data; Development; Diabetes Mellitus; Diagnosis; FOXO1A gene; Failure; Fasting; Female; Fetus; Financial compensation; Gestational Diabetes; Glucose; Glucose Intolerance; Goals; Health; Hormones; Hyperglycemia; Impairment; Insulin; Insulin Resistance; Knockout Mice; Link; Mediating; Metabolic stress; Modeling; Mothers; Mus; Nuclear; Nutritional; Outcome; Pathway interactions; Phosphorylation; Physiological; Plasma; Play; Pregnancy; Pregnant Women; Prolactin; Prolactin Receptor; Protein Tyrosine Kinase; Receptor Signaling; Regulation; Risk; Role; Signal Transduction; Structure of beta Cell of islet; Techniques; Third Pregnancy Trimester; Weight Gain; Wild Type Mouse; euglycemia; forkhead protein; glucose metabolism; hormonal signals; impaired glucose tolerance; in vivo; insight; insulin secretion; insulin signaling; islet; maternal weight; pregnant; response; single-cell RNA sequencing; transcription factor; transcriptome; transcriptome sequencing

Abstract: Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without previously diagnosed diabetes. GDM affects up to 10% of all pregnancies, imposing a significant adverse effect on the health of both mother and fetus. To date, the underlying mechanism of GDM remains elusive. Pregnancy is commonly associated with insulin resistance in the mother, a physiological response that serves to spare blood glucose supplies for the fetus. To overcome insulin resistance, pancreatic β-cells of pregnant mothers release more insulin into the blood. Such an adaptive response, termed “β-cell compensation”, is essential for maintaining normal blood glucose metabolism in pregnancies. In at-risk pregnant women, β-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. Nonetheless, how β-cells compensate for maternal insulin resistance during pregnancy and what causes β-cell failure in GDM are poorly understood. To decipher the mechanism of β-cell compensation for pregnancy, we determined gestational regulation of β-cell mass and function by FoxO1 - a key transcription factor that integrates insulin signaling and nutritional cues to cell metabolism, survival, proliferation and differentiation. We found that β-cell FoxO1 expression is markedly upregulated, coinciding with the physiological induction of β-cell compensation in mice during pregnancy. Furthermore, we showed that β-cell FoxO1 deficiency predisposes pregnant female mice to GDM, as evidenced by the induction of impaired glucose tolerance, elevated blood glucose levels and reduced glucose-stimulated insulin secretion during pregnancy. These new data underscore the importance of FoxO1 in governing the adaptive changes of β-cell mass and function in response to pregnancy, spurring the hypothesis that FoxO1 deregulation may be the missing link between maternal insulin resistance and β-cell decompensation in GDM. To address this hypothesis, we will use rigorous in vivo and ex vivo studies to characterize the role of FoxO1 in integrating gestational hormonal signaling to adaptive changes in β-cell mass and function during pregnancy. We will determine the mechanism by which FoxO1 augments β-cell compensation for maternal insulin resistance in female mice. Furthermore, we will determine the mechanism of how β-cell FoxO1 deficiency causes β-cell decompensation, contributing to the development of GDM. Accomplishing this project will deepen our understanding of gestational β-cell compensation for maternal insulin resistance, providing new mechanistic insights into β-cell decompensation and GDM.

摘要： 妊娠期糖尿病（GDM）的特征是孕妇的葡萄糖耐受不良， 以前诊断的糖尿病。GDM影响高达10%的所有妊娠，造成显著的不利影响。 对母亲和胎儿健康的影响。到目前为止，GDM的潜在机制仍然难以捉摸。 怀孕通常与母亲的胰岛素抵抗有关，这是一种生理反应， 为胎儿提供充足的血糖供应为克服胰岛素抵抗， 母亲会向血液中释放更多的胰岛素。这种适应性反应，称为“β细胞补偿”， 对维持妊娠期正常血糖代谢至关重要。在高危孕妇中，β细胞 不能补偿母体胰岛素抵抗，导致胰岛素不足和GDM。尽管如此， β细胞如何补偿怀孕期间母体的胰岛素抵抗，以及是什么导致β细胞衰竭， 对GDM了解甚少。为了解释β细胞对妊娠的补偿机制，我们确定了 FoxO 1-整合胰岛素的关键转录因子对妊娠期β细胞质量和功能的调节 信号传导和营养提示细胞代谢、存活、增殖和分化。我们发现β细胞 FoxO 1表达显著上调，与β细胞代偿的生理诱导一致 在怀孕期间的小鼠。此外，我们还发现β细胞FoxO 1缺乏易使妊娠女性 GDM小鼠，如通过诱导葡萄糖耐量受损、血糖水平升高和 减少妊娠期间葡萄糖刺激的胰岛素分泌。这些新数据强调了以下方面的重要性： FoxO 1在控制β细胞质量和功能的适应性变化中对妊娠的反应，刺激妊娠， FoxO 1失调可能是母体胰岛素抵抗和β细胞 GDM的失代偿为了解决这一假设，我们将使用严格的体内和体外研究， 表征FoxO 1在整合妊娠激素信号传导至β细胞群适应性变化中的作用 和功能。我们将确定FoxO 1增强β细胞的机制， 补偿雌性小鼠的母体胰岛素抵抗。此外，我们将确定 β细胞FoxO 1缺乏如何导致β细胞代偿失调，从而导致GDM的发展。 该项目的完成将加深我们对妊娠期β细胞代偿的理解， 胰岛素抵抗，为β细胞失代偿和GDM提供了新的机制见解。